The invention relates to benzimidazole derivatives of formula (I) 
wherein the groups X, R1, R2, R3 and R4 may have the meanings given in the claims and specification, processes for preparing them and the use of benzimidazole derivatives as pharmaceutical compositions, particularly as pharmaceutical compositions with a tryptase-inhibiting activity.
Benzimidazole derivatives are known from the prior art as active substances having valuable pharmaceutical properties. Thus, International Patent Application WO 98/37075 discloses, in addition to other bicyclic heterocycles, benzimidazoles which can be used to good effect for the prevention and treatment of venous and arterial thrombotic diseases, on the basis of their thrombin-inhibiting activity.
In contrast to the use of benzimidazole derivatives as described above and known from the prior art, the aim of the present invention is to prepare new tryptase-inhibitors which can be used, on the basis of their tryptase-inhibiting properties, for the prevention and treatment of inflammatory and/or allergic diseases.
It is therefore an object of the invention to provide benzimidazole derivatives of formula (I) 
wherein the groups X, R1, R2, R3 and R4 may have the meanings given in the claims and specification, processes for preparing them and the use of benzimidazole derivatives as pharmaceutical compositions, particularly as pharmaceutical compositions with a tryptase-inhibiting activity.
Surprisingly, it has been found that benzimidazole derivatives of general formula (I) wherein the groups R1, R2, R3 and R4 may have the meanings given hereinafter have a tryptase-inhibiting effect and may be used according to the invention for the prevention and treatment of diseases in which tryptase-inhibitors may develop a therapeutic benefit.
The present invention thus relates to benzimidazole derivatives of formula (I) 
wherein
R1 denotes a group selected from among C1-C12-alkyl, C2-C12-alkenyl and C2-C12-alkynyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, halogen, xe2x80x94CO(C1-C12-alkoxy), xe2x80x94COxe2x80x94NR5R6, xe2x80x94NR5R6 or C1-C1 2-alkoxy-phenoxy, or phenyl-C1-C12-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C12-alkoxy, carboxy, halogen, C1-C12-alkoxycarbonyl or CF3, or
xe2x80x83a 5- or 6-membered, saturated or unsaturated heterocyclic group linked directly or via a C1-C12-alkylene bridge, which may contain one or two heteroatoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C1-C12-alkyl or benzyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes a hydrogen atom or a C1-C12-alkyl group which may optionally be mono- or disubstituted by one or two groups selected from among xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-6-alkyl, furanyl, benzofuranyl, thiophenyl, benzothiophenyl, anthracenyl, phenyl, pyridyl and naphthyl, while the abovementioned aromatic and heteroaromatic substituents in turn may each be mono-, di- or trisubstituted by one or more of the groups selected from among C1-C12-alkyl, C1-C12-alkoxy, halogen, xe2x80x94C1-C12-alkyl-halogen, xe2x80x94NH2, xe2x80x94NH(C1-C12-alkyl), xe2x80x94N(C1-C12-alkyl)2, NO2, hydroxy, xe2x80x94CF3, xe2x80x94NHCOxe2x80x94C1-C12-alkyl, xe2x80x94COOH, xe2x80x94COO(C1-C12-alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C12-alkyl), xe2x80x94CON(C1-C12-alkyl)2, xe2x80x94CONH(C1-C12-alkyl)-COO(C1-C12-alkyl) and phenyl-C1-C12-alkyl;
X denotes  greater than Cxe2x95x90O,  greater than CH2 or xe2x80x94CH2CH2xe2x80x94;
R4 denotes a group of formula (A) 
W denotes N or CH;
A denotes NR6 when n=0, and denotes O, CHR6 or NR6 when n=1;
R5 and R6 independently of one another each denote a hydrogen atom or a group of formula
xe2x80x94Bxe2x80x94(CO)mxe2x80x94, 
wherein
B denotes a C1-C12-alkyl, C3-C8-cycloalkyl, phenyl, naphthyl or a fluorenyl group or a 5- or 6-membered heterocyclic group containing nitrogen, oxygen and/or sulphur, wherein the group B may optionally be substituted in each case by one or more groups selected from among halogen, halo-C1-C12-alkyl, halo-C1-C12-alkoxy, xe2x80x94OH, C1-C12-alkyl, C1-C12-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, xe2x80x94COxe2x80x94Oxe2x80x94H, xe2x80x94COxe2x80x94Oxe2x80x94C1-C12-alkyl, xe2x80x94NO2, pyrrolidin-1-yl, piperidin-1-yl, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C12-alkyl, xe2x80x94NH-phenyl, xe2x80x94NH-pyridyl, xe2x80x94N(C1-C12-alkyl)2 and xe2x80x94C(xe2x95x90NH)NH2, and
m denotes 0 or 1, or
R5 and R6 together with the nitrogen atom attached form a 5- to 8-membered heterocyclic group, which may be substituted by a group selected from among halogen, halo-C1-C12-alkyl, xe2x80x94OH, xe2x80x94C1-C12-alkyl, C1-C12-alkoxy, phenoxy, benzyloxy, xe2x80x94COxe2x80x94Oxe2x80x94C1-C12-alkyl, xe2x80x94NO2, phenyl, pyrrolidin-1-yl, piperidin-1-yl, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C12-alkyl, xe2x80x94NH-pyridyl, xe2x80x94N(C1-C12-alkyl)2 and xe2x80x94C(xe2x95x90NH)NH2,
n is 0 or 1;
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The term alkyl groups (including those which are part of other groups, especially alkoxy), unless otherwise stated, denotes branched and unbranched alkyl groups with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, most preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. Examples are: methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. Unless otherwise stated, the above terms propyl, butyl, pentyl or hexyl also include all the possible isomeric forms. For example, the term propyl also includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl, neopentyl, etc. In some cases common abbreviations are also used to denote the abovementioned alkyl groups, such as Me for methyl, Et for ethyl etc.
The term haloalkyl groups (including those which are part of other groups, especially haloalkoxy), unless otherwise stated, denotes branched and unbranched haloalkyl groups with 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, which are substituted by at least one halogen atom, particularly fluorine atom. Fluorinated groups of the formula
xe2x80x94(CH2)pxe2x80x94(CF2)qxe2x80x94Y 
wherein
p denotes 0 or an integer from 1 to 4,
q denotes an integer from 1 to 4, and
Y denotes hydrogen or fluorine, are preferred.
Examples include: trifluoromethyl, trifluoromethoxy, difluoromethoxy, perfluoroethyl, perfluoropropyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1,1,1-trifluoroprop-2-yl, etc.
The term alkenyl groups (including those which are part of other groups) denotes branched and unbranched alkenyl groups having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, particularly 2 to 4 carbon atoms, provided that they have at least one double bond, for example the alkyl groups mentioned above as well, provided that they have at least one double bond, such as for example vinyl (provided that no unstable enamines or enolethers are formed), propenyl, iso-propenyl, butenyl, pentenyl and hexenyl.
The term alkynyl groups (including those which are part of other groups) denotes alkynyl groups having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, particularly 2 to 4 carbon atoms provided that they have at least one triple bond, e.g. ethynyl, propargyl, butynyl, pentynyl and hexynyl.
The term halogen generally denotes fluorine, chlorine, bromine or iodine.
The term xe2x80x9c5- or 6-membered heterocyclic group containing nitrogen, oxygen and/or sulphurxe2x80x9d as used in connection with the group B, generally denotes an aromatic or saturated group having 5 or 6 cyclic atoms, wherein at least one cyclic atom is a heteroatom selected from among N, O and S, which may optionally be fused to another cyclic system.
The term xe2x80x9c5- to 8-membered heterocyclic groupxe2x80x9d as used for the group formed by R5 and R6 together with the enclosed nitrogen atom, generally denotes a saturated nitrogen-containing group having 5 to 8 cyclic atoms, which may optionally contain one or more heteroatoms selected from among N, O and S.
The following are mentioned as examples of particular heterocyclic groups: acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl, azanaphthacenyl, azanaphthalenyl, azaprenyl, azatriphenylenyl, azepinyl, azinoindolyl, azinopyrrolyl, benzacridinyl, benzazapinyl, benzofuryl, benzonaphthyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl, benzothiepinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl, caprolactamyl, carbazolyl, carbolinyl, catechinyl, chromenopyronyl, chromonopyranyl, cumarinyl, cumaronyl, decahydroquinolinyl, decahydroquinolonyl, diazaanthracenyl, diazaphenanthrenyl, dibenzazapinyl, dibenzofuranyl, dibenzothiphenyl, dichromylenyl, dihydrofuranyl, dihydroisocumarinyl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridonyl, dihydropyronyl, dihydrothiopyranyl, diprylenyl, dioxanthylenyl, oenantholactamyl, flavanyl, flavonyl, fluoranyl, fluoresceinyl, furanedionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydrofuranonyl, hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl, indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofuranedionyl, isobenzofuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobenzazapinyl, isoindolyl, isoquinolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, naphthalenyl, naphthimidazopyridindionyl, naphthindolizinedionyl, naphthodihydropyranyl, naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl, phenanthraquinonyl, phthalideisoquinolinyl, phthalimidyl, phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyranedionyl, pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridinethionyl, pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl, pyridoquinolinyl, pyronyl, pyrrocolinyl, pyrrolidinyl, pyrrolizidinyl, pyrrolizinyl, pyrrolodioazinyl, pyrrolonyl, pyrrolopyrmidinyl, pyrroloquinolonyl, pyrrolyl, quinacridonyl, quinolinyl, quinolizidinyl, quinolizinyl, quinolonyl, quinuclidinyl, rhodaminyl, spirocumaranyl, succinimidyl, sulpholanyl, sulpholenyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiapyranyl, tetrahydrothiophenyl, tetrahydrothipyranonyl, tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl, thiadecalinyl, thianaphthenyl, thiapyranyl, thiapyronyl, thiazolopyridinyl, thienopyridinyl, thienopyrrolyl, thienothiophenyl, thiepinyl, thiochromenyl, thiocumarinyl, thiopyranyl, triazaanthracenyl, triazinoindolyl, triazolopyridinyl, tropanyl, xanthenyl, xanthonyl, xanthydrolyl, adeninyl, alloxanyl, alloxazinyl, anthranilyl, azabenzanthrenyl, azabenzonaphthenyl, azanaphthacenyl, azaphenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzocinnolinyl, benzodiazocinyl, benzodioxolanyl; benzodioxolyl, benzopyridazinyl, benzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl, depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxazolyl, dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl, dioxanyl, dioxenyl, dioxepinyl, dioxinonyl, dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, dithiolanyl, dithiolenyl, dithiolyl, flavinyl, furopyrimidinyl, glycocyamidinyl, guaninyl, hexahydropyrazinoisoquinolinyl, hexahydropyridazinyl, hydantoinyl, hydroimidazolyl, hydroparazinyl, hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, imidazolinyl, imidazolyl, imidazoquinazolinyl, imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl, lumazinyl, methylthyminyl, methyluracilyl, morpholinyl, naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl, oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl, oxazolyl, perhydrocinnolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhydrothiazinonyl, perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenoxazonyl, phthalazinyl, piperazinedionyl, piperazinodionyl, polyquinoxalinyl, pteridinyl, pterinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinethionyl, pyrimidinyl, pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydroquinoxalinyl, tetrahydrothiazolyl, thiazepinyl, thiazinyl, thiazolidinonyl, thiazolidinyl, thiazolinonyl, thiazolinyl, thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl, thiazolidinonyl, thyminyl, triazolopyrimidinyl, uracilyl, xanthinyl, xylitolyl, azabenzonapththenyl, benzofuroxanyl, benzothiadiazinyl, benzotriazepinonyl, benzotriazolyl, benzoxadiazinyl, dioxadiazinyl, dithiadazolyl, dithiazolyl, furazanyl, furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl, oxadiazolyl, oxathiazinonyl, oxatriazolyl, pentazinyl, pentazolyl, pentazinyl, polyoxadiazolyl, sydonyl, tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, thiadiazinyl, thiadiazolinyl, thiadiazolyl, thiadioxazinyl, thiatriazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, trithiadiazepinyl, trithianyl or trioxolanyl.
Examples of particularly preferred 5-, 6- or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulphur as heteroatoms include, for example, furan, tetrahydrofuran, tetrahydrofuranone, xcex3-butyrolactone, xcex1-pyran, xcex3-pyran, dioxolan, tetrahydropyran, dioxan, thiophene, dihydrothiophene, thiolan, dithiolan, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole and pyrazolidine, unless otherwise specified in the definitions, wherein the heterocyclic group may be substituted as stated in the definitions.
Compounds of formula (I), wherein X denotes  greater than Cxe2x95x90O, W denotes N and A denotes NR6, are preferred.
m is preferably 0, and n is preferably 1.
R5 is preferably naphthyl, particularly naphth-2-yl, pyridyl, particularly pyrid-2-yl or pyrid-3-yl or a phenyl group optionally substituted by one or two halogen atoms, particularly selected from the formula 
wherein
L1 denotes a fluorine, chlorine, bromine or iodine atom, and
L2 and L3 independently of one another each denote a hydrogen, fluorine or chlorine atom.
Preferred compounds according to the invention are the compounds of formula (I), wherein
R1 denotes a C1-C6-alkyl group, particularly methyl, ethyl, propyl or butyl, which may optionally be mono, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, halogen, xe2x80x94CO(C1-C4-alkoxy), xe2x80x94COxe2x80x94NR5R6, xe2x80x94NR5R6 or C1-C4-alkoxy-phenoxy.
Also preferred are compounds of formula (I), wherein R4 denotes a group of formula (A),
A denotes NR6,
R5 denotes a C1-C4-alkyl, phenyl, naphthyl, fluorenyl, pyridyl, pyrrolidinyl or benzyl group, while these groups may each optionally be substituted by one, two or three groups selected from among halogen, xe2x80x94OH, halo-C1-C4-alkyl, halo-C1-C4-alkoxy, C1-C4-alkyl, C1-C4-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, xe2x80x94COxe2x80x94OH, xe2x80x94COxe2x80x94Oxe2x80x94C1-C4-alkyl, xe2x80x94NO2, pyridyl, pyrrolidin-1-yl, piperidin-1-yl, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C4-alkyl, and
R6 denotes a hydrogen atom or a C1-C4-alkyl group.
Particularly preferred are the compounds of formula (I), wherein R1 denotes methyl, ethyl or propyl; and
R4 denotes a group of formula (A1) 
X denotes  greater than Cxe2x95x90O;
R5 denotes a hydrogen atom or a C1-C4-alkyl, C1-C4-alkanoyl, phenyl, naphthyl, fluorenyl, anthracenyl, pyridyl, pyrrolidinyl or benzyl group, while these groups may each optionally be substituted by one or more groups, preferably one or two groups selected from among halogen, halo-C1-C4-alkyl, halo-C1-C4-alkoxy, xe2x80x94OH, C1-C4-alkyl, C1-C4-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, xe2x80x94COxe2x80x94Oxe2x80x94C1-C4-alkyl, xe2x80x94NO2, pyridyl, pyrrolidin-1-yl, piperidin-1-yl, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94N(C1-C4-alkyl)2 and xe2x80x94C(xe2x95x90NH)NH2, and
R6 denotes a hydrogen atom or a C1-C4-alkyl group.
Also preferred are benzimidazole derivatives of general formula (I), wherein
R1 denotes C1-C4-alkyl, which may optionally be mono, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, halogen, xe2x80x94CO(C1-C4-alkoxy or C1-C4-alkoxy-phenoxy,
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes methyl, xe2x80x94CH2xe2x80x94COOH, xe2x80x94CH2xe2x80x94COOxe2x80x94C1-C4-alkyl, naphthylmethyl, benzyl or pyridylmethyl, which may be substituted at the particular aromatic and heteroaromatic ring by a group selected from among C1-C6-alkyl, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl) and xe2x80x94N(C1-C4-alkyl)2,
R4 denotes a group of formula (A), wherein A is NR6;
X denotes  greater than Cxe2x95x90O;
R5 denotes methyl, ethyl, propyl, butyl, phenyl, naphthyl, pyridyl or benzyl, which may optionally be substituted by one or two groups selected from among halogen, trifluoromethyl, trifluoromethoxy, methyl, xe2x80x94OH, methoxy, xe2x80x94NO2, phenyl, naphthyl, pyrrolidin-1-yl, xe2x80x94NH2, xe2x80x94NH-methyl, xe2x80x94N(methyl)2, xe2x80x94NH-ethyl, xe2x80x94N(ethyl)2 and xe2x80x94C(xe2x95x90NH)NH2,
R6 denotes hydrogen, methyl, ethyl, propyl or butyl,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are benzimidazole derivatives of formula (I), wherein
R1 denotes methyl, ethyl, propyl or butyl, preferably methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes methyl, xe2x80x94CH2xe2x80x94COOH, xe2x80x94CH2xe2x80x94COO-ethyl, naphthylmethyl, benzyl or pyridylmethyl,
R4 denotes a group of formula (A1);
X denotes  greater than Cxe2x95x90O;
R5 denotes phenyl, naphthyl, pyridyl or benzyl, which may optionally be substituted by one or two groups selected from among fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, xe2x80x94OH, methoxy and phenyl,
R6 denotes hydrogen or methyl,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Also particularly preferred are benzimidazole derivatives of formula (I), wherein
R1 denotes methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes methyl, xe2x80x94CH2xe2x80x94COOH, xe2x80x94CH2xe2x80x94COO-ethyl, naphthylmethyl, benzyl or pyridylmethyl;
R4 denotes a group of formula (A1);
X denotes  greater than Cxe2x95x90O;
R5 denotes phenyl, naphthyl, pyridyl or benzyl, which may optionally be substituted by one or two groups selected from among fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, xe2x80x94OH, methoxy and phenyl,
R6 denotes hydrogen or methyl,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of particular importance according to the invention are benzimidazole derivatives of formula (I), wherein
R1 denotes methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes methyl, xe2x80x94CH2xe2x80x94COOH, xe2x80x94CH2xe2x80x94COO-ethyl, benzyl, naphth-1-ylmethyl or pyrid-4-ylmethyl;
R4 denotes a group of formula (A1);
X denotes  greater than Cxe2x95x90O;
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are the compounds of formulae (IA) and (IB) 
wherein in each case
R3 denotes hydrogen, xe2x80x94CH2xe2x80x94COOH, xe2x80x94CH2xe2x80x94COO-ethyl, methyl, butyl, benzyl, pyridylmethyl or naphthalinylmethyl, wherein the aromatic groups may be substituted in each case by C1-C6-alkyl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C4-alkyl, or xe2x80x94N(C1-C4-alkyl)2;
R5 denotes a C1-C4-alkyl, C1-C4-alkanoyl, phenyl, pyridyl, benzoyl or pyridylcarbonyl group, while these groups may each optionally be substituted by one or more, preferably one, two or three, particularly one or two groups selected from among halogen, xe2x80x94OH, xe2x80x94C1-C4-alkyl, C1-C4-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, xe2x80x94COxe2x80x94Oxe2x80x94C1-C4-alkyl, xe2x80x94NO2, phenyl, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C4-alkyl and xe2x80x94N(C1-C4-alkyl)2, and
R6 denotes a hydrogen atom or a methyl group,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
In addition to the abovementioned compounds of general formula (I) the present invention also relates to compounds which are only converted into the therapeutically effective compounds of general formula (I) by the body after being taken by the patient, on the basis of a functionality which can be cleaved in vivo. Such compounds are known as prodrugs. According to another aspect the invention therefore relates to prodrugs of general formula (II) 
wherein
X, R1, R3 and R4 are as hereinbefore defined and
R7 denotes hydroxy, xe2x80x94COOxe2x80x94C1-C12alkyl, xe2x80x94COOxe2x80x94C1-C12-haloalkyl, xe2x80x94CO-phenyl, xe2x80x94CO-pyridyl, xe2x80x94COO-phenyl or xe2x80x94COOxe2x80x94C1-C8-alkyl-phenyl, wherein in the abovementioned groups the phenyl ring may be substituted in each case by C1-C4-alkyl, C1-C4-alkoxy, OH, halogen, xe2x80x94NH2, C1-C4-alkyl-NH, di-(C1-C4-alkyl)N or CF3,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred are prodrugs of formula (II), wherein
R7 denotes hydroxy, xe2x80x94COOxe2x80x94C1-C6-alkyl, xe2x80x94COOxe2x80x94C1-C6-haloalkyl, xe2x80x94CO-phenyl, xe2x80x94CO-pyridyl, xe2x80x94COO-phenyl or xe2x80x94COOxe2x80x94C1-C6-alkyl-phenyl, wherein in the abovementioned group the phenyl ring may be substituted in each case by C1-C4-alkyl, C1-C4-alkoxy, OH, halogen or CF3,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are prodrugs of general formula (II), wherein
R7 denotes hydroxy, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, butyloxycarbonyl, benzoyl, benzyloxycarbonyl or nicotinoyl,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The present invention is further directed to the use of the compounds of general formula (I) as hereinbefore defined and the prodrugs of general formula (II) for preparing a pharmaceutical composition for the treatment of diseases in which tryptase inhibitors may be of therapeutic benefit.
It is preferred according to the invention to use compounds of general formula (I) for the purpose mentioned above, for preparing a pharmaceutical composition for the prevention and/or treatment of inflammatory and/or allergic diseases. It is particularly preferable to use the compounds of general formula (I) as mentioned above to prepare a pharmaceutical composition for the prevention and/or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders, Crohn""s disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
It is also advantageous to use the compounds of general formula (I) as mentioned above for preparing a pharmaceutical composition for the prevention and/or treatment of diseases with reconstruction processes in the airways and the lung parenchyma such as chronic (obstructive) bronchitis and interstitial lung diseases such as idiopathic lung fibrosis, fibrosing alveolitis, sarcoidosis and histiocytosis X and other fibrosing diseases such as scarring, and also collagenoses such as lupus erythematodes and scierodermia as well as arteriosclerosis, psoriasis and neoplasia.
The substituted benzimidazole derivatives of formula (I) as well as the prodrugs of general formula (II) may be obtained by various methods of synthesis. Possible approaches based on and using conventional methods of chemical synthesis are hereinafter described by way of example. Diagram 1 shows one possible method of synthesising the basic benzimidazole structure of the compounds according to the invention. 
Diagram 1:
Starting from the 2-halo-5-nitro-anilines (1) aminolysis may be carried out first to obtain the diaminonitrobenzoles (2) according to Diagram 1 (step i). The aminolysis of the compounds (1) with the primary amines R1xe2x80x94NH2 is carried out in suitable organic solvents such as for example dimethylsulphoxide, N,N-dimethylformamide, N-methylpyrrolidone, acetone or optionally also in water or alcohols at ambient temperature or in a temperature range from 30-80xc2x0 C., preferably 40-50xc2x0 C.
The reaction of the compounds (2) with p-cyanophenylpropionic acid leads to the nitro-benzimidazoles (3, step ii) in the presence of dehydrating reagents. The reaction is optionally carried out in a solvent or mixture of solvents such as acetic acid, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan. Suitable dehydrating agents include for example isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilan, phosphorus oxychloride, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, ethyl 1,2-dihydro-2-ethoxy-quinoline-1-carboxylate (EEDQ), i-propyl 1,2-dihydro-2-1-propyloxy-quinoline-1-carboxylate (IIDQ), N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride. It may be appropriate to add a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine. The reaction is usually carried out at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 20 and 120xc2x0 C.
The nitrobenzimidazole derivatives (3) obtained according to the procedure described above may be reductively converted into the aminobenzimidazoles (4) (step iii, Diagram 1). The reduction of the nitro group to form the compounds (3) is carried out for example by catalytic hydrogenation in organic solvents such as for example methanol, ethanol, isopropanol, tetrahydrofuran, optionally also in admixture with dimethylformamide, ethyl acetate, dioxan or acetic acid, at elevated hydrogen pressure or at normal pressure at temperatures between 0-50xc2x0 C., preferably at 20-40xc2x0 C. Suitable catalysts are conventional hydrogenation catalysts. Palladium and Raney nickel are preferred. According to the invention, palladium is preferred. Palladium on charcoal (5%) is particularly preferred as the catalyst. An alternative method of reducing the nitro compounds (3) envisages the use of reduction agents such as Na2S2O4 or SnCl2. This reaction is carried out in protic, water-miscible organic solvents such as short-chained alcohols (methanol, ethanol, isopropanol) or in a mixture of the abovementioned solvents with water, optionally with acetic acid, dimethylformamide or ethyl acetate. The reaction is normally carried out at elevated temperature, preferably by refluxing the solvent or solvent mixture in question. After the reaction of the starting compounds (3) is complete, the mixture is worked up in the usual way. The compounds (4) may be purified for example by crystallisation from nonpolar organic solvents such as diethylether, petroleum ether, optionally mixed with ethyl acetate.
Starting from the benzimidazoles (4) which may be obtained according to Diagram 1, the compounds (5) according to Diagram 2 are obtained by reaction with the compounds R3xe2x80x94Nu, where Nu denotes a nucleofugic leaving group such as for example chlorine, bromine, iodine, methanesulphonate, methyltriflate, p-toluenesulphonate etc. Alternatively, the compounds (5) may be obtained starting from the compounds (4) by the method of reductive amination by reacting with correspondingly substituted ketones or aldehydes under reductive conditions. 
Diagram 2:
In order to react the compounds (4) with R3xe2x80x94Nu according to step iv the following procedure may be used. A compound (4) is dissolved in a polar solvent, such as dimethylformamide, dimethylactamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and most preferably anhydrous, possibly absolute dimethylformamide. The solution thus obtained is combined with a base and the corresponding alkylating agent R3xe2x80x94Nu. The base used may be an alkali or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. It is also possible to use the alkali or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohol or water. The reaction mixture is stirred for 0.5-8 h, preferably 1-4 h at elevated temperature, preferably at 50-120xc2x0 C., particularly at the reflux temperature of the solvent used. After the reaction is complete the mixture is worked up in the usual way and the crude product obtained is purified by crystallisation or chromatography on silica gel.
If the compounds (5) are obtained from the compounds (4) by reductive amination, the following procedure is used. The compound (4) is dissolved in a suitable solvent such as for example dichloromethane, dichloroethane, methanol, ethanol, tetrahydrofuran or toluene, and at between 0-60xc2x0 C., preferably at 20-40xc2x0 C., the corresponding carbonyl compound is added in the presence of an acid, preferably a carboxylic acid, most preferably a short-chained carboxylic acid, particularly acetic acid. Then a suitable reduction agent is added. Suitable reduction agents which may be used according to the invention are Na[HB(OAc)3], Na[BH3CN], NaBH4, Pd/Cxe2x80x94H2, preferably Na[HB(OAc)3]. After working up in the usual way the product is purified by crystallisation or chromatography on silica gel.
The intermediates of general formula (III) wherein n is 1 may be obtained from the compounds (5), as shown in Diagram 3, by acylation (step va) or alkylation (step vb). 
Diagram 3:
The reaction of the compounds (5) with the chloroacetic acid to obtain the intermediates of general formula (III) may be carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C.
Alternatively, the intermediates of general formula (III) may also be obtained by standard methods by reacting with alkylating reagents R4xe2x80x94CH2X1 (with X1: halide, mesylate, tosylate, etc.) or activated carboxylic acid derivatives R4xe2x80x94COX2 (with X2: halide, alkoxy, etc.) in the abovementioned solvents or mixtures of solvents in the presence of bases such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine.
The compounds (IIIA) may be reacted with the amines according to step vi to form the intermediates (III). The compound (IIIA) is dissolved in a polar solvent, such as dimethylformamide, dimethylactamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and most preferably anhydrous, possibly absolute dimethylformamide. The solution thus obtained is combined with a base and the corresponding amine. The base used may be an alkali or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. The reaction mixture is stirred for 0.5-8 h, preferably 1-4 h at elevated temperature, preferably at 50-120xc2x0 C., particularly at the reflux temperature of the solvent used. After the reaction is complete the mixture is worked up in the usual way and the crude product obtained is purified by crystallisation or chromatography on silica gel.
The intermediates of general formula (III) wherein R6 denotes hydrogen and is 0, [?] may be obtained from the compounds (5), as shown in Diagram 4, by reacting with the corresponding isocyanates. The compounds of formula (III) wherein R6 is other than hydrogen may be obtained by alkylation with an alkylating reagent R6xe2x80x94X3 (with X3: halide, mesylate, tosylate, etc.) or by reductive amination by the methods described in connection with Diagram 2. 
Diagram 4:
The compounds of formula (I) according to the invention may be obtained from the intermediates (III) according to step vii in Diagram 5. 
Diagram 5:
In order to prepare the compounds of general formula (I) according to the invention wherein R2 denotes xe2x80x94C(xe2x95x90NH)NH2, various procedures may be used.
A compound of general formula (I) is obtained for example by treating a compound of general formula (III) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol optionally mixed with another organic solvent such as for example chloroform, nitrobenzene or toluene in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxan at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequent aminolysis with alcoholic ammonia solution, for example. Alternatively, the compounds of general formula (I) may be obtained by reacting a compound of general formula (III) with sulphur nucleophiles such as e.g. hydrogen sulphide, ammonium or sodium sulphide, sodium hydrogen sulphide, carbon disulphide, thioacetamide or bistrimethylsilylthioether, optionally in the presence of bases such as triethylamine, ammonia, sodium hydride or sodium alkoxide in solvents such as methanol, ethanol, water, tetrahydrofuran, pyridine, dimethylformamide or 1,3-dimethyl-imidazolidin-2-one at 20-100xc2x0 C., and subsequent treatment with a suitable methylating agent such as e.g. methyliodide or dimethylsulphate in a solvent such as acetonitrile or acetone at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C., and subsequent treatment with ammonia, ammonium carbonate or ammonium chloride in a suitable alcohol, such as for example methanol, ethanol, isopropanol etc. at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C.
Moreover, the compounds of general formula (I) according to the invention may be obtained by treating a compound of general formula (III) with lithium hexamethyl disilazide in a suitable organic solvent such as e.g. tetrahydrofuran at temperatures between xe2x88x9220 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequently hydrolysing with dilute hydrochloric acid at 0-5xc2x0 C.
Another alternative method of obtaining compounds of general formula (I) is by treating a compound of general formula (III) with ammonium chloride and trimethylaluminium in a suitable organic solvent such as e.g. toluene at temperatures between 20 and 150xc2x0 C., but preferably at 110xc2x0 C.
Compounds of general formula (I) wherein R2 denotes xe2x80x94CH2xe2x80x94NH2 may be obtained from the intermediates (III) for example by catalytic hydrogenation on Raney nickel. These reactions are preferably carried out in protic organic solvents such as short-chained alcohols (methanol, ethanol or isopropanol) at temperatures between 10-40xc2x0 C., preferably at 20-30xc2x0 C. under normal pressure.
A compound of general formula (II) is obtained for example by treating a compound of general formula (III, Diagram 3, step vii) with hydroxylamine in the presence of carbonates or alkoxides of alkali or alkaline earth metals in solvents such as methanol, ethanol, n-propanol or isopropanol optionally in admixture with dioxan or tetrahydrofuran. The alkoxides may be prepared from the respective alkali metals or metal hydrides and the corresponding alcohol. The reaction is preferably carried out at 20-100xc2x0 C., most preferably at the boiling temperature of the solvent used.
Compounds of general formula (II) may alternatively be obtained by treating a compound of general formula (III) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxan at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequently treating with hydroxylamine in the presence of bases in a suitable alcohol, such as methanol, ethanol, isopropanol etc. at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C.
A compound of general formula (I) is obtained for example by treating a compound of general formula (II), (Diagram 3, step viii) with hydrogen in the presence of hydrogenation catalysts such as Raney nickel or rhodium/aluminium oxide in water or methanol, optionally with the addition of acids such as hydrochloric acid or methanesulphonic acid or by treating with hydrogen in the presence of palladium/charcoal in acetic acid/acetic anhydride at 20-50xc2x0 C. and 1-5 bar hydrogen pressure, preferably at ambient temperature and normal pressure.
The acyl- or alkoxycarbonyl prodrugs (II) of the compound of general formula (I) are obtained by reacting the compounds of general formula (I) with the corresponding acid chlorides in the presence of bases such as e.g. triethylamine, N-methyl morpholine, diethylisopropylamine or DBU in a suitable solvent such as methylene chloride, chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or dimethylsulphoxide.
In accordance with their central role in the synthesis of the compounds of general formula (I) according to the invention as well as the synthesis of the prodrugs of general formula (II), a further aspect of the present invention is directed to the intermediates of general formula (III) 
wherein the groups X, R1, R3 and R4 are as hereinbefore defined.
The compounds of general formula (III) are valuable intermediates for preparing the benzimidazole derivatives of general formula (I) according to the invention as well as the prodrugs of general formula (II) according to the invention.
By virtue of their pharmacological properties, the compounds according to the invention may be used as pharmaceutical compositions, particularly as pharmaceutical compositions with a tryptase-inhibiting activity. They may be used wherever tryptase inhibitors may be of therapeutic benefit.
It is preferred according to the invention to use compounds of general formula (I) to prepare a pharmaceutical composition for the prevention and/or treatment of inflammatory and/or allergic diseases. It is particularly preferable to use the compounds of general formula (I) as mentioned above to prepare a pharmaceutical composition for the prevention and/or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders, Crohn""s disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
It is also advantageous to use the compounds of general formula (I) as mentioned above for preparing a pharmaceutical composition for the prevention and/or treatment of fibroses such as lung fibrosis, fibrosing alveolitis and scarring, collagenoses such as lupus erythematodes and sclerodermia as well as arteriosclerosis, psoriasis and neoplasia.
Procedures by way of example for preparing the compounds according to the invention will be described in more detail hereinafter. The Examples which follow serve solely as a detailed illustration without restricting the subject matter of the invention.